Field of the Invention and Description of the Prior Art
This invention is concerned with improvements in and relating to pharmaceutical compositions, nutritional supplements, and diagnostics. More particularly, it is concerned with such compositions in dosage unit form encapsulated in soft elastic gelatin (SEG) capsules.
Pharmaceutical compositions in dosage unit form encapsulated in SEG capsules are well known and generally consist of a fill material comprising one or more active agents dissolved or suspended in an appropriate liquid or paste vehicle, encapsulated in a soft gelatin shell, typically comprising gelatin together with a plasticizer. Manufacture of SEG capsules requires the fill material to be a pumpable liquid or paste. The carrier liquid can be a single or a multi-component system that must be compatible with the SEG capsule.
Liquids used in SEG capsules fall into two general categories, hydrophilic and lipophilic. There are many examples of acceptable lipophilic liquids used in the SEG format. Usually these are oils and are not water soluble. Due to the poor solubility of lipophilic liquids in water and gastric medium, they tend to have poor dispersion properties in the stomach, however. For this reason, formulations of pharmaceutical active ingredients and lipophilic carriers can retard the release of these active ingredients into the gastric fluid. It is often advantageous to prepare the active ingredients in solution for reasons of improved bioavailability and faster onset of action. Unfortunately, lipophilic liquids are poor solvents for many pharmaceutical active ingredients. These disadvantages can be overcome by using hydrophilic liquids.
There are few hydrophilic liquids suitable for use as carrier liquids in this application. The most versatile of these carriers in general use is polyethylene glycol, particularly in the molecular weight range of 200-800. This material offers good dispersion in gastric medium, excellent solubilizing capabilities for pharmaceutical active ingredients and good compatibility in the SEG format. However, there are disadvantages to using this material. One major disadvantage is that of instability; polyethylene glycol while in the presence of atmospheric oxygen reacts to form aldehydes. The residual aldehyde content of polyethylene glycol will react with the gelatin shell causing the protein polymers to inter- and intra-crosslink. The net result is a crosslinked gelatin shell that is insoluble in gastric media. To reduce this problem, polyethylene glycol must be handled in an inert atmosphere, for example, under a nitrogen blanket. Polyethylene glycol is also implicated as a potential irritant to mucous membranes found in the gastrointestinal tract.
Another class of hydrophilic liquids is non-ionic surfactants. These also have the disadvantage of being potential mucous membrane and stomach irritants. Common examples of materials in this category are polysorbate 80 and polysorbate 20. Legislation permits only small quantities of these materials to be ingested daily in over-the-counter and nutritional supplement products. This can restrict the use of these materials as a major component of a carrier system. A further disadvantage of non-ionic surfactants is that their inherent surface activity can have an adverse effect on the formation of the capsule seals, leading to a leaking product.
Sugar solutions are another category of hydrophilic carrier liquids. However, concentrated sugar solutions, such as glucose syrup, sorbitol solution and maltose syrup, are not particularly suitable for this application due to their adverse effect on gelatin capsules. Sorbitol causes excessive plasticization of the gelatin wall leading to deterioration of the capsule. Concentrated sugar solutions containing reducing sugars are also incompatible with gelatin. The reason is that the reactive aldehyde isomers of reducing sugars will cause gelatin crosslinking and unacceptable Maillard browning reactions. Common reducing sugars are dextrose and fructose which are present in glucose and maltose syrups. Also, concentrated aqueous solutions of sucrose are not sufficiently hygroscopic to retain water within an SEG capsule leading to distorted capsule shapes and crystalline sugar in the fill. Concentrated sugar solutions do have the advantage over previous examples of not being mucous membrane irritants, but some examples can cause some gastric disturbances due to their potential laxative properties when ingested in large amounts. This is particularly true of sorbitol.
U.S. Pat. No. 4,935,243 is directed to chewable, edible soft gelatin capsules with a shell of water, gelatin, plasticizer and hydrogenated starch hydrolysate, added to render the shell dispersible and soluble in the mouth. The SEG capsule contains a fill material with an active ingredient dispersed or dissolved in it. The hydrogenated starch hydrolysate in the capsule shell, which is used to augment the taste and chewability of the shell, is said to include hydrolysates "which contain less than 3% of polyols whose degree of polymerization (DP) is higher than 20, about 35-60% of maltitol (DP 2), about 0.1-20% of sorbitol (DP 1), and the balance being constituted by a mixture of polyols of DP 3-20."
U.S. Pat. No. 4,465,667 describes suspensions of aluminum hydroxide based antacid components in suspension form, stabilized with a hydrogenated hydrolysed glucose polymer in an amount of 2-30% by weight. Stabilizing agents disclosed include "a sugar alcohol [sic]as xylitol, mannitol, sorbitol or glycerol, by mixture of sugar alcohols obtained at the preparation of xylitol or a sugar such as glucose, maltose, fructose, or saccharose." Examples of specific stabilizing agents for the antacid suspension include LYCASIN.RTM., the trademark for a syrup prepared by catalytic hydrogenation or reduction of a high maltose syrup obtained by the enzymatic hydrolysis of food starch. LYCASIN.RTM. is available from Roquette Corporation, Gurnee, Ill.
U.S. Pat. No. 2,580,683, issued Jan. 1, 1952, is directed to "a stable gelatin capsule inclosing an aqueous solution having hygroscopic material present in a quantity of a magnitude preventing deterioration of the capsule by the aqueous constituent of the solution."